Disease relevance of TP53BP1

• We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22) [1].
• We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia [1].
• 53BP1 contains two breast cancer susceptibility gene 1 COOH terminus (BRCT) motifs, which are present in several proteins involved in DNA repair and/or DNA damage-signaling pathways [2].
• In untreated primary cells and U2OS osteosarcoma cells, 53BP1 exhibited diffuse nuclear staining; whereas, within 5-15 min after exposure to ionizing radiation (IR), 53BP1 localized at discreet nuclear foci [3].
• Here, we show that E2F1-mediated apoptosis induced by the infection of an E2F1-expressing adenoviral vector (Ad-E2F1) was greatly diminished in p202-expressing prostate cancer cells [4].

High impact information on TP53BP1

• Using a human cell line that faithfully recapitulated the Chk2-p53-PUMA pathway, we show that USP28 is required to stabilize Chk2 and 53BP1 in response to DNA damage [5].
• Histone lysine methylation has been linked to the recruitment of mammalian DNA repair factor 53BP1 and putative fission yeast homolog Crb2 to DNA double-strand breaks (DSBs), but how histone recognition is achieved has not been established [6].
• Using X-ray crystallography and nuclear magnetic resonance (NMR) spectroscopy, we show that, despite low amino acid sequence conservation, both 53BP1 and Crb2 contain tandem tudor domains that interact with histone H4 specifically dimethylated at Lys20 (H4-K20me2) [6].
• The acceleration of NHEJ was unlikely to be due to increased presence of 53BP1 and Mre11 in TIFs, since knockdown of neither factor affected telomere fusions [7].
• The DNA-damage response protein 53BP1 has two BRCT domains that bind to the DNA-binding domain of p53 [8].

Chemical compound and disease context of TP53BP1

• 53BP1 1347_1352delTATCCC, leading to the loss of an isoleucine and a proline residue, showed a nonsignificant inverse association with breast cancer risk (odds ratio = 0.61, 95% confidence interval = 0.22 to 1.68, P = 0.34) [9].
• We showed that parenteral administration of an ARR2PB-p202/liposome preparation led to prostate-specific p202 expression and tumor suppression in orthotopic prostate cancer xenograft model [10].

Biological context of TP53BP1

• Here, we report that 53BP1 becomes hyperphosphorylated and forms discrete nuclear foci in response to DNA damage [2].
• The LC8-binding domain was mapped to a short peptide segment immediately N-terminal to the kinetochore localization region of 53BP1 [11].
• 53BP1 is required for at least a subset of ataxia telangiectasia-mutated (ATM)-dependent phosphorylation events at sites of DNA breaks and for cell cycle arrest at the G2-M interphase after exposure to irradiation [12].
• This checkpoint protects against apoptosis because depletion of 53BP1 or p21(WAF1/CIP1) increases both the rate and extent of apoptosis [13].
• E2F1-induced MRN foci are similar to irradiation-induced foci (IRIF) that result from double-strand DNA breaks because they correlate with 53BP1 and gammaH2AX foci, do not form in NBS cells, do form in AT cells and do not correlate with cell cycle entry [13].

Anatomical context of TP53BP1

• Fibroblast cells treated with methylase inhibitors failed to relocalize 53BP1 to sites of DNA damage and formed few gamma-H2AX foci, consistent with our previous data that MRE11 fails to relocalize to DNA damage sites in cells treated with methylase inhibitors [14].
• Silencing of HDAC4 via RNA interference surprisingly also decreased levels of 53BP1 protein, abrogated the DNA damage-induced G2 delay, and radiosensitized HeLa cells [15].
• Enhanced intra-switch region recombination during immunoglobulin class switch recombination in 53BP1(-/-) B cells [16].
• Microwaves from GSM mobile telephones affect 53BP1 and gamma-H2AX foci in human lymphocytes from hypersensitive and healthy persons [17].
• The expression of the MDM2 gene, a p53 binding protein, in thyroid carcinogenesis [18].

Associations of TP53BP1 with chemical compounds

• 53BP1 foci formation is not restricted to gamma-radiation but is also detected in response to UV radiation as well as hydroxyurea, camptothecin, etoposide, and methylmethanesulfonate treatment [2].
• This binding was inhibited by the replacement in p202 of a histidine (from the M(F/L)HATVA(T/S) sequence that is conserved among all of the 200 family proteins) by phenylalanine [19].
• The hyperphosphorylation of 53BP1 after treatment with nocodazole, a microtubule-interfering agent, was monitored by immunoblotting [20].
• Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2 [21].
• The 53BP1-PDGFRbeta fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRbeta [1].

Physical interactions of TP53BP1

• The interaction is augmented in a phospho-dependent manner, and the MDC1 binding region of 53BP1 is phosphorylated in vivo in mitotic cells; therefore, it is probably modulated by cell cycle-regulated kinases [22].

Enzymatic interactions of TP53BP1

• Third, 53BP1 is readily phosphorylated by ATM in vitro [2].
• Like many proteins involved in the DNA damage response, 53BP1 becomes hyperphosphorylated after radiation and colocalizes with phosphorylated H2AX in megabase regions surrounding the sites of DNA strand breaks [23].

Co-localisations of TP53BP1

• Phosphorylated DNA-PKcs colocalizes with both gamma-H2AX and 53BP1 after DNA damage [24].

Regulatory relationships of TP53BP1

• Several observations suggest that 53BP1 is regulated by ataxia telangiectasia mutated (ATM) after DNA damage [2].
• Disruption of the interaction between LC8 and 53BP1 in vivo prevented DNA damage-induced nuclear accumulation of p53 [11].
• Here we report that expression of p202 inhibited E2F-4/DP-1-stimulated transcription of a reporter gene in transfected cells [25].
• Inhibition of E2F-4/DP-1-stimulated transcription by p202 [25].
• Forced expression of MCT-1 significantly increases the number of DNA damage-induced foci involving gamma-H2AX and 53BP1 [26].

Other interactions of TP53BP1

• Taken together, these results suggest that 53BP1 is an ATM substrate that is involved early in the DNA damage-signaling pathways in mammalian cells [2].
• Unlike other known LC8-binding proteins, 53BP1 contains two distinct LC8-binding motifs that are arranged in tandem [11].
• Therefore, 53BP1 can potentially act as an adaptor to assemble p53 to the dynein complex [11].
• Whether 53BP1 and NFBD1 are required for activation of kinases and/or for recruitment of substrates at IRIF, however, is not clear [27].
• However, it is not known whether E2F1-mediated apoptosis can be counteracted by p202 expression [4].
• Our data suggest that TP53BP1 variants may have protective effects on SCCHN risk but such effects were confined to TP53 variant allele/haplotype carriers [28].

Analytical, diagnostic and therapeutic context of TP53BP1

• To examine whether 53BP1 has a role in the cellular response to DNA damage, we probed its intracellular localization by immunofluorescence [3].
• Indirect immunofluorescence studies also indicated that the human Snm1 protein colocalized with 53BP1 before and after exposure to ionizing radiation, and a physical interaction was confirmed by coimmunoprecipitation assays [29].
• NFBD1, like 53BP1, is an early and redundant transducer mediating Chk2 phosphorylation in response to DNA damage [30].
• The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR [1].
• Purification, crystallization and preliminary X-ray analysis of the BRCT domains of human 53BP1 bound to the p53 tumour suppressor [31].

References